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Search Results: 1 - 10 of 467066 matches for " Melissa A Brown "
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Gene therapy by electroporation for the treatment of chronic renal failure in companion animals
Patricia A Brown, Angela M Bodles-Brakhop, Melissa A Pope, Ruxandra Draghia-Akli
BMC Biotechnology , 2009, DOI: 10.1186/1472-6750-9-4
Abstract: Plasmid-treated animals showed an increase in body weight (dogs 22.5% and cats 3.2%) compared to control animals, and displayed improved quality of life parameters including significant increases in appetite, activity, mentation and exercise tolerance levels. Insulin-like growth factor I (IGF-I, the downstream effector of GHRH) levels were increased in the plasmid treated animals. Hematological parameters were also significantly improved. Protein metabolism changes were observed suggesting a shift from a catabolic to an anabolic state in the treated animals. Blood urea nitrogen and creatinine did not show any significant changes suggesting maintenance of kidney function whereas the control animal's renal function deteriorated. Treated animals survived longer than control animals with 70% of dogs and 80% of cats surviving until study day 75. Only 17% and 40% of the control dogs and cats, respectively, survived to day 75.Improved quality of life, survival and general well-being indicate that further investigation is warranted, and show the potential of a plasmid-based therapy by electroporation in preventing and managing complications of renal insufficiency.Renal failure and its complications, such as anemia and decreased life expectancy, can be related to primary kidney disease, such as glomerulonephritis or pyelonephritis, or are a consequence of long-term chronic diseases such as cancer, hypertension, heart failure, diabetes or severe allergic reactions [1,2]. The predicted increase in the number of people with renal failure and end-stage renal disease places an enormous burden on the healthcare provider system [3]. Strategies are therefore needed to improve the prevention, detection [4] and treatment of kidney disease.Chronic renal failure (CRF) can affect the growth hormone releasing hormone/growth hormone/insulin-like growth factor-I (GHRH/GH/IGF-I) axis [5] which can lead to growth retardation in children and is associated with increased morbidity and mortality
Investigation of the human pathogen Acinetobacter baumannii under iron limiting conditions
Bart A Eijkelkamp, Karl A Hassan, Ian T Paulsen, Melissa H Brown
BMC Genomics , 2011, DOI: 10.1186/1471-2164-12-126
Abstract: Under low iron conditions, transcription levels were more than 2-fold up-regulated for 463 genes, including 95 genes that were up-regulated more than 4-fold. Of particular significance, three siderophore biosynthesis gene clusters, including one novel cluster, were highly up-regulated. Binding sites for the ferric uptake regulator were identified in the promoter regions of many up-regulated genes, suggesting a prominent role for this regulator in the Acinetobacter iron acquisition response. Down-regulation under iron limitation was less dramatic as the transcription of only 202 genes varied more than 2-fold. Various genes involved in motility featured prominently amongst the genes down-regulated when iron was less readily available. Motility assays confirmed that these transcriptional changes are manifested at the phenotypic level. The siderophore biosynthesis gene clusters were further investigated by means of comparative genomic analysis of 10 sequenced Acinetobacter isolates. These analyses revealed important roles for mobile genetic elements in shaping the siderophore meditated iron acquisition mechanisms between different Acinetobacter strains.A. baumannii grown under iron limited conditions resulted in major transcriptional changes of not only many iron acquisition related genes, but also genes involved in other processes such as motility. Overall, this study showed that A. baumannii is well adaptable to growth in an environment which has limiting iron availability.An increasing prevalence of infections caused by Acinetobacter baumannii has been observed in the clinical setting throughout the last 10 to 15 years [1,2]. A. baumannii is able to persist in the hospital environment and in particular intensive care units, due to its wide variety of resistance mechanisms and high survival rate on abiotic surfaces [3-6]. Some clinical A. baumannii strains have been shown to be naturally competent for the uptake of genetic material, which facilitates acquisition of no
Functional analyses reveal an important role for tyrosine residues in the staphylococcal multidrug efflux protein QacA
Jingqin Wu, Karl A Hassan, Ronald A Skurray, Melissa H Brown
BMC Microbiology , 2008, DOI: 10.1186/1471-2180-8-147
Abstract: Determination of the resistance profiles and analysis of drug transport assays revealed that non-conservative substitutions for most tyrosine residues influenced the QacA drug recognition spectrum. However, an aromatic residue at three tyrosine positions, 63, 410 and 429, was of importance for QacA-mediated transport and resistance to the majority of substrates tested.A tyrosine or phenylalanine residue at amino acid positions corresponding to 63 of QacA in related drug efflux proteins is found to be highly conserved. Therefore, an aromatic side chain at this position is likely to partake in a function common to these drug transporters, such as proton translocation or essential intramolecular contacts, whereas aromatic residues at the non-conserved 410 and 429 positions are expected to mediate a QacA-specific function, possibly forming or stabilising part of the QacA drug binding region.The QacA multidrug efflux protein confers resistance to at least 30 structurally distinct monovalent or bivalent cationic lipophilic antimicrobials from at least 12 different chemical families [1,2]. Furthermore, genes encoding qacA or a highly related derivative are carried by widespread clinical isolates of the human pathogen Staphylococcus aureus[3-5]. Therefore, the QacA multidrug resistance protein facilitates an efflux mechanism by which strains of S. aureus may currently overcome control measures, such as the use of biocides within the clinical environment, and spread to new hosts [1,3].The QacA polypeptide is composed of 514 amino acid residues, organised into 14 α-helical transmembrane segments (TMS) (Figure 1) [6,7] and is classified as a member of the drug:H+ antiporter (DHA) 2 family of the major facilitator superfamily (MFS) of transport proteins [8]. Drug efflux mediated by QacA is powered by the proton-motive-force and can be described using Michaelis-Menton kinetics [9]. The drug binding region within QacA appears to contain distinct binding sites for monovalent and b
Adherence: a review of education, research, practice, and policy in the United States
Rickles,Nathaniel M.; Brown,Todd A.; McGivney,Melissa S.; Snyder,Margie E.; White,Kelsey A.;
Pharmacy Practice (Internet) , 2010, DOI: 10.4321/S1886-36552010000100001
Abstract: objective: to describe the education, research, practice, and policy related to pharmacist interventions to improve medication adherence in community settings in the united states. methods: authors used medline and international pharmaceutical abstracts (since 1990) to identify community and ambulatory pharmacy intervention studies which aimed to improve medication adherence. the authors also searched the primary literature using ovid to identify studies related to the pharmacy teaching of medication adherence. the bibliographies of relevant studies were reviewed in order to identify additional literature. we searched the tables of content of three us pharmacy education journals and reviewed the american association of colleges of pharmacy website for materials on teaching adherence principles. policies related to medication adherence were identified based on what was commonly known to the authors from professional experience, attendance at professional meetings, and pharmacy journals. results: research and practice: 29 studies were identified: 18 randomized controlled trials; 3 prospective cohort studies; 2 retrospective cohort studies; 5 case-controlled studies; and one other study. there was considerable variability in types of interventions and use of adherence measures. many of the interventions were completed by pharmacists with advanced clinical backgrounds and not typical of pharmacists in community settings. the positive intervention effects had either decreased or not been sustained after interventions were removed. although not formally assessed, in general, the average community pharmacy did not routinely assess and/or intervene on medication adherence. education: national pharmacy education groups support the need for pharmacists to learn and use adherence-related skills. educational efforts involving adherence have focused on students′ awareness of adherence barriers and communication skills needed to engage patients in behavioral change. policy: sever
A Single Acidic Residue Can Guide Binding Site Selection but Does Not Govern QacR Cationic-Drug Affinity
Kate M. Peters,Benjamin E. Brooks,Maria A. Schumacher,Ronald A. Skurray,Richard G. Brennan,Melissa H. Brown
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0015974
Abstract: Structures of the multidrug-binding repressor protein QacR with monovalent and bivalent cationic drugs revealed that the carboxylate side-chains of E90 and E120 were proximal to the positively charged nitrogens of the ligands ethidium, malachite green and rhodamine 6G, and therefore may contribute to drug neutralization and binding affinity. Here, we report structural, biochemical and in vivo effects of substituting these glutamate residues. Unexpectedly, substitutions had little impact on ligand affinity or in vivo induction capabilities. Structures of QacR(E90Q) and QacR(E120Q) with ethidium or malachite green took similar global conformations that differed significantly from all previously described QacR-drug complexes but still prohibited binding to cognate DNA. Strikingly, the QacR(E90Q)-rhodamine 6G complex revealed two mutually exclusive rhodamine 6G binding sites. Despite multiple structural changes, all drug binding was essentially isoenergetic. Thus, these data strongly suggest that rather than contributing significantly to ligand binding affinity, the role of acidic residues lining the QacR multidrug-binding pocket is primarily to attract and guide cationic drugs to the “best available” positions within the pocket that elicit QacR induction.
Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts
Phillip J Whiley, Christopher A Pettigrew, Brooke L Brewster, Logan C Walker, kConFab Investigators, Amanda B Spurdle, Melissa A Brown
BMC Medical Genetics , 2010, DOI: 10.1186/1471-2350-11-80
Abstract: This study used a combination of RT-PCR analysis and splicing reporter minigene assays to assess five unclassified variants in the BRCA2 gene that we had previously predicted to disrupt an ESE using bioinformatic approaches.Analysis of BRCA2 c.8308 G > A (p.Ala2770Thr) by mRNA analysis, and BRCA2 c.8962A > G (p.Ser2988Gly), BRCA2 c.8972G > A (p.Arg2991His), BRCA2 c.9172A > G (p.Ser3058Gly), and BRCA2 c.9213G > T (p.Glu3071Asp) by a minigene assay, revealed no evidence for aberrant splicing.These results illustrate the need for improved methods for predicting functional ESEs and the potential consequences of sequence variants contained therein.DNA sequence variants of unknown clinical significance are regularly identified when individuals with a family history of breast cancer are screened for mutations in the BRCA1 and BRCA2 genes. Determining the clinical relevance of these unclassified variants, particularly rare exonic unclassified variants, is challenging. Currently, functional assays designed to assess the pathogenicity of exonic unclassified variants usually aim to determine the effect on protein function, and do not take into account the potential effect the UV may have on RNA function. Defects in RNA function, including defects in RNA splicing, stability and translation, are likely to underly the pathogenicity of a significant proportion of unclassified variants (reviewed in [1]). For example, sequence variants in exonic splice enhancers (ESEs) that result in either abnormal splicing or induce the skipping and therefore rescue of deleterious non-sense mutations, have previously been reported in multiple disease-associated genes, including BRCA1 and BRCA2 [2-6],Whilst predicting the consequences of unclassified variants in the consensus donor and acceptor dinucleotide sites flanking exons can be done with reasonable confidence, forecasting the effect of exonic unclassified variants mapping to ESEs is much more difficult. This is in part due to fact that ESEs
Evolutionary conservation analysis increases the colocalization of predicted exonic splicing enhancers in the BRCA1 gene with missense sequence changes and in-frame deletions, but not polymorphisms
Christopher Pettigrew, Nicola Wayte, Paul K Lovelock, Sean V Tavtigian, Georgia Chenevix-Trench, Amanda B Spurdle, Melissa A Brown
Breast Cancer Research , 2005, DOI: 10.1186/bcr1324
Abstract: As an initial step toward determining which ESEs predicted by the web-based tool ESEfinder in the breast cancer susceptibility gene BRCA1 are likely to be functional, we have determined their evolutionary conservation and compared their location with known BRCA1 sequence variants.Using the default settings of ESEfinder, we initially detected 669 potential ESEs in the coding region of the BRCA1 gene. Increasing the threshold score reduced the total number to 464, while taking into consideration the proximity to splice donor and acceptor sites reduced the number to 211. Approximately 11% of these ESEs (23/211) either are identical at the nucleotide level in human, primates, mouse, cow, dog and opossum Brca1 (conserved) or are detectable by ESEfinder in the same position in the Brca1 sequence (shared). The frequency of conserved and shared predicted ESEs between human and mouse is higher in BRCA1 exons (2.8 per 100 nucleotides) than in introns (0.6 per 100 nucleotides). Of conserved or shared putative ESEs, 61% (14/23) were predicted to be affected by sequence variants reported in the Breast Cancer Information Core database. Applying the filters described above increased the colocalization of predicted ESEs with missense changes, in-frame deletions and unclassified variants predicted to be deleterious to protein function, whereas they decreased the colocalization with known polymorphisms or unclassified variants predicted to be neutral.In this report we show that evolutionary conservation analysis may be used to improve the specificity of an ESE prediction tool. This is the first report on the prediction of the frequency and distribution of ESEs in the BRCA1 gene, and it is the first reported attempt to predict which ESEs are most likely to be functional and therefore which sequence variants in ESEs are most likely to be pathogenic.Studies of the pathogenicity of nucleotide sequence variants in disease-associated genes usually focus on the effect on encoded protein str
Persistence of West Nile Virus in the Central Nervous System and Periphery of Mice
Kim K. Appler,Ashley N. Brown,Barbara S. Stewart,Melissa J. Behr,Valerie L. Demarest,Susan J. Wong,Kristen A. Bernard
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010649
Abstract: Most acute infections with RNA viruses are transient and subsequently cleared from the host. Recent evidence, however, suggests that the RNA virus, West Nile virus (WNV), not only causes acute disease, but can persist long term in humans and animal models. Our goal in this study was to develop a mouse model of WNV persistence. We inoculated immunocompetent mice subcutaneously (s.c.) with WNV and examined their tissues for infectious virus and WNV RNA for 16 months (mo) post-inoculation (p.i.). Infectious WNV persisted for 1 mo p.i. in all mice and for 4 mo p.i. in 12% of mice, and WNV RNA persisted for up to 6 mo p.i. in 12% of mice. The frequency of persistence was tissue dependent and was in the following order: skin, spinal cord, brain, lymphoid tissues, kidney, and heart. Viral persistence occurred in the face of a robust antibody response and in the presence of inflammation in the brain. Furthermore, persistence in the central nervous system (CNS) and encephalitis were observed even in mice with subclinical infections. Mice were treated at 1 mo p.i. with cyclophosphamide, and active viral replication resulted, suggesting that lymphocytes are functional during viral persistence. In summary, WNV persisted in the CNS and periphery of mice for up to 6 mo p.i. in mice with subclinical infections. These results have implications for WNV-infected humans. In particular, immunosuppressed patients, organ transplantation, and long term sequelae may be impacted by WNV persistence.
Multifactorial Likelihood Assessment of BRCA1 and BRCA2 Missense Variants Confirms That BRCA1:c.122A>G(p.His41Arg) Is a Pathogenic Mutation
Phillip J. Whiley, Michael T. Parsons, Jennifer Leary, Kathy Tucker, Linda Warwick, Belinda Dopita, Heather Thorne, Sunil R. Lakhani, David E. Goldgar, Melissa A. Brown, Amanda B. Spurdle
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0086836
Abstract: Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg) RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1), nine were likely not pathogenic (Class 2), and one was uncertain (Class 3).These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies.
The Use of Life Narrative and Living Standard Measurement Survey Data in the Study of Poverty in the Caribbean: A Resolution of Conflicting Epistemologies  [PDF]
Dennis A. V. Brown
Sociology Mind (SM) , 2013, DOI: 10.4236/sm.2013.33030
Abstract:

The paper examines the compatibility or usefulness of fit between epistemologically disparate quantitative survey data and qualitative life narrative data gleaned in the study of poverty in the Caribbean. It aims to find out whether or not the different approaches to the understanding of reality on which the two methodologies are based preclude the integration of their findings as a means of furthering understanding of the dynamics of Caribbean poverty. The analysis draws on Country Poverty Studies conducted in the territory of Grenada in the Eastern Caribbean. It is centered on the demographic measure of fertility, a measure of chronic illnesses by socioeconomic status and life narrative interviews conducted around the themes of poverty, family and life experiences with select poor households across the country. Fertility was measured using parity of women aged <15 - 30+. Statistical analyses were done using cross tabulations. The findings indicate that the hermeneutic understanding of the life narratives, and the causal explanatory accounts provided by the positivist quantitative data, allow for understanding of negative health seeking behaviour on the part of the poor, not provided by the quantitative data by themselves. They also provide insight into the synergy between family, reproductive behaviour, labour market status and chronic poverty in the Caribbean region that would not have been possible through the use of the positivist quantitative method by itself.

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